Common variable immunodeficiency is a rare immune deficiency, characterized by low levels of serum immunoglobulin G, A, and/or M with loss of antibody production. The diagnosis is most commonly made in adults between the ages of 20 and 40 years, but both children and older adults can be found to have this immune defect. The range of clinical manifestations is broad, including acute and chronic infections, inflammatory and autoimmune disease, and an increased incidence of cancer and lymphoma. For all these reasons, the disease phenotype is both heterogeneous and complex. Contributing to the complexity is that patient cohorts are generally small, criteria used for diagnosis vary, and the doses of replacement immune globulin differ. In addition, routines for monitoring patients over the years and protocols for the use of other biologic agents for complications have not been clarified or standardized. In the past few years, data from large patient registries have revealed that both selected laboratory markers and clinical phenotyping may aid in dissecting groups of subjects into biologically relevant categories. This review presents my approach to the diagnosis and treatment of patients with common variable immunodeficiency, with suggestions for the use of laboratory biomarkers and means of monitoring patients.
Common variable immunodeficiency (CVID) is the most common clinically important primary immune deficiency disease because of its prevalence, estimated to be between 1 in 25 000 to 50 000 white patients, complications, hospitalizations, and requirement for lifelong replacement immunoglobulin (Ig) therapy. 1 ,2 Unlike many genetic immune defects, most subjects diagnosed with CVID are adults between the ages of 20 and 40 years, although many are found outside this age range. Although the syndrome was first described more than 50 years ago, 3 the diagnosis is still commonly delayed by 6 to 8 years, even after the onset of characteristic symptoms. A number of reports 1 ,4 –8 of cohorts of subjects with CVID have appeared. In appropriate doses, Ig replacement reduces the incidence of acute bacterial infections; however, Ig does not address the more problematic of complications that have now emerged as the foremost concerns, including chronic lung disease, systemic granulomatous disease, autoimmunity, lymphoid hyperplasia and infiltrative disease, gastrointestinal disease, and the development of cancer. These complications now appear to be the major cause of morbidity and death in patients with CVID. 1 ,9 This review is intended as a personal summary of how I assess patients at the outset and an outline for how one may monitor and treat some of these challenging complications.
Diagnosis of CVID
The diagnosis of CVID (International Classification of Diseases code 279.06) is often misused. It is defined as a genetic immune defect
characterized by significantly decreased levels of immunoglobulin G (IgG), immunoglobulin A (IgA), and/or immunoglobulin M (IgM) with poor or absent antibody production, with exclusion of genetic or other causes of hypogammaglobulinemia. 1 ,2 ,9 ,10 On the basis of the standard definition, antibody deficiency with normal Ig levels, or IgG deficiency alone, would not qualify for the diagnosis of CVID. Because CVID is not always easily discerned from transient hypogammaglobulinemia of infancy, a general consensus is that this diagnosis should not be applied until after a patient reaches the age of 4. This allows time for the immune system to mature, and if necessary, for one to consider the possibility of other genetic primary immune defects. However, the published criteria still leave open rather wide boundaries. First laboratory standards for normal ranges differ; in addition, the use of the 95% percentile for Ig allows 2.5% of normal subjects to fall below the normal range.
Sometimes forgotten, the additional necessary criteria for CVID also include a proven lack of specific IgG antibody production, which is usually demonstrated by lack of IgG responses (not attaining laboratory-defined protective levels) to 2 or more protein vaccines, such as tetanus or diphtheria toxoids, Hemophilus conjugate, measles, mumps, and rubella vaccines, and also by a lack of response to pneumococcal polysaccharide vaccines. Other options for protein antigens include hepatitis A or B vaccines or varicella, either after vaccination or disease exposure. Examining blood for pertinent isohemagglutins is another a common means of testing (mostly) IgM anticarbohydrate antibody production in older children and adults.
Although extensive antibody testing is not as important for subjects with very low serum IgG (potentially ≤150 mg/dL), those with greater levels of serum IgG (450-600 mg/dL), and especially those with only minimally reduced serum IgA, require more extensive evaluation. It is more likely that these subjects have preservation of IgG antibody production and are therefore less likely to benefit from Ig therapy. A suggested template for such analyses is given in Table 1. Demonstration of persistence of IgG antibody at 6 months after vaccination can be important to prove sustained antibody production in some cases. The many reasons for a very thorough evaluation before the diagnosis of CVID include the fact that the diagnosis of CVID has an impact on short- and long-term insurance coverage, influences the outcome of all subsequent medical encounters, and may alter school and job choices and other life decisions, such as family planning and travel. In addition, if replacement Ig therapy is initiated without a compete evaluation and the use of this therapy is later questioned, it must be stopped for approximately 5 months before such an evaluation can be performed.